Influence of hepatic and intestinal cytochrome P4503A activity on the acute disposition and effects of oral transmucosal fentanyl citrate

Anesthesiology. 2004 Sep;101(3):729-37. doi: 10.1097/00000542-200409000-00022.


Background: Oral transmucosal fentanyl citrate (OTF) was developed to provide rapid analgesia and is specifically approved for treating breakthrough cancer pain. Fentanyl in OTF is absorbed across the oral mucosa, but a considerable portion is swallowed and absorbed enterally. Fentanyl metabolism is catalyzed by cytochrome P4503A4 (CYP3A). The role of intestinal or hepatic first-pass metabolism and CYP3A activity in OTF disposition is unknown. This investigation examined the influence of hepatic and intestinal CYP3A activity on the disposition and clinical effects of OTF.

Methods: Healthy volunteers (n = 12) were studied in an Institutional Review Board-approved, randomized, balanced, four-way crossover. They received OTF (10 microg/kg) after hepatic/intestinal CYP3A induction by rifampin, hepatic/intestinal CYP3A inhibition by troleandomycin, selective intestinal CYP3A inhibition by grapefruit juice, or nothing (control). Plasma fentanyl and norfentanyl concentrations were determined by mass spectrometry. Fentanyl effects were measured by dark-adapted pupil diameter and subjective self-assessments using visual analog scales.

Results: : Peak plasma fentanyl concentrations, time to peak, and maximum pupil diameter change from baseline were unchanged after rifampin, troleandomycin, and grapefruit juice. Fentanyl elimination, however, was significantly affected by CYP3A alterations. After control, rifampin, troleandomycin and grapefruit juice, respectively, area under the curve of plasma fentanyl versus time was 5.9 +/- 3.7, 2.2 +/- 0.8,* 10.4 +/- 8.9,* and 5.8 +/- 3.3 h x ng/ml; norfentanyl/fentanyl plasma area under the curve ratios were 0.92 +/- 0.63, 3.2 +/- 1.8,* 0.08 +/- 0.14,* and 0.67 +/- 0.33 (*P < 0.05 versus control).

Discussion: Peak fentanyl concentrations and clinical effects after OTF were minimally affected by altering both intestinal and hepatic CYP3A activity, whereas fentanyl metabolism, elimination, and duration of effects were significantly affected; selective intestinal CYP3A inhibition had minimal effects. This suggests that first-pass metabolism minimally influences OTF bioavailability. When treating breakthrough pain, with careful attention to maximal mucosal absorption and minimal swallowing, CYP3A variability and drug interactions are unlikely to affect the onset or magnitude of OTF analgesia; however, duration may be affected.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacokinetics*
  • Analgesics, Opioid / pharmacology*
  • Antibiotics, Antitubercular / pharmacology
  • Antiemetics / pharmacology
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Beverages
  • Chromatography, High Pressure Liquid
  • Citrus
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Drug Interactions
  • Female
  • Fentanyl / administration & dosage
  • Fentanyl / analogs & derivatives*
  • Fentanyl / blood
  • Fentanyl / pharmacokinetics*
  • Fentanyl / pharmacology*
  • Food-Drug Interactions
  • Half-Life
  • Humans
  • Intestines / enzymology*
  • Liver / enzymology*
  • Male
  • Oxidoreductases, N-Demethylating / metabolism*
  • Pupil / drug effects
  • Rifampin / pharmacology
  • Spectrometry, Mass, Electrospray Ionization
  • Troleandomycin / pharmacology


  • Analgesics, Opioid
  • Antibiotics, Antitubercular
  • Antiemetics
  • norfentanyl
  • Troleandomycin
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Fentanyl
  • Rifampin